It is known that the neurotransmitter, N-Acetyl-aspartyl-glutamate (NAAG), which is found throughout the nervous system, is enzymatically converted to the potentially exitotoxic neurotransmitter, glutamate, by the enzyme .alpha.-linked acidic dipeptidase (NAALADase), also known as NAAG-hydrolyzing enzyme, in both normal and in pathophysiological conditions of the neurological system. (A new name was recently proposed for NAALADase: glutamate carboxypepsidase II.) Under current practice, drugs are used to block glutamate at its receptor "downstream". However, there has not previously been an adequate method for blocking the enzymatic formation of glutamate from an immediate precursor, NAAG.
It is believed that NAAG is released in response to neuronal trauma/ischemic injury, and is then hydrolyzed to form glutamic acid. Because NAAG has only a fraction of the excitatory potency of glutamic acid, the concentration of NAAG required to be neurotoxic might be 100-fold the toxic concentration of glutamic acid.
At present, spinal injury, whether arising from trauma or disease, disables many Americans of all ages. There has previously been no really effective therapeutic agent for use in treatment of such CNS injuries. Injuries such as those arising from penetrating injuries, exposure to blast, blunt trauma, falls and vehicular accidents as well as spinal cord and brain injury secondary to decompression sickness are examples of instances when use of PMPA, .alpha.-NAAG or .beta.-NAAG in accord with the teachings of this disclosure would be appropriate. Any damage which results in hypoxia, including ischemia and toxicity, can cause severe damage to the neuronal tissue.
A neuronal tissue that is particularly subject to damage arising from hypoxia, ischemia, exposure to toxins or any other causes of degeneration is the retina.
The leading causes of blindness in the United States include age-related macular degeneration (AMD), diabetic retinopathy, glaucoma and cataracts. The prevalence of diabetes in North America is expected to reach almost 17 million by the year 2000. In cases of insulin-dependent diabetes mellitus (IDDM) with onset before age 30, the average prevalence of proliferative retinopathy is estimated at 23%. In the case of IDDM of more than 30 years duration, however the incidence of proliferative retinopathy rises to 70%. Proliferative retinopathy is the leading cause of new cases of blindness in the U.S., accounting for 12% of new cases annually.
The prevalence of AMD increases from over 2% in the age group 60-64 years to over 25% in the 75-80 year age group. It: is estimated that the prevalence of glaucoma in the United States will be 2.9 million by the year 2000, and that over 130,000 will have been blinded by this disease.
At present, eye drops are available for treating vernal conjunctivitis containing both .alpha.- and .beta.-NAAG. .beta.-NAAG is a very weak NAALADase inhibitor that also has been found to act as an agonist. (ANAAG is also an agonist.) Thus, .beta.-NAAG is not a specific NAALADase inhibitor. However, neither .alpha.-NAAG nor .beta.-NAAG were previously known to have use in treating or preventing damage to the retina or other neuronal tissue.